CN101605544A - CRTH2 antagonists - Google Patents

Abstract

The following compounds are CRTH2 antagonists and are useful for treating respiratory diseases: [ 3- (2, 4-dichlorophenylsulfanyl) -6-fluoro-2-methylindolizin-1-yl ] acetic acid, [ 6-fluoro-3- (2-fluoro-4-methanesulfonylphenylsulfanyl) -2-methylindolizin-1-yl ] acetic acid, [ 6-fluoro-3- (4-methanesulfonyl-2-trifluoromethylphenylsulfanyl) -2-methylindolizin-1-yl ] acetic acid, (R) -2- [ 6-fluoro-3- (4-methanesulfonylphenylsulfanyl) -2-methylindolizin-1-yl ] propionic acid, [ 3- (4-ethanesulfonylphenylsulfanyl) -6-fluoro-2-methylindolizin-1-yl ] acetic acid, (S) -2- [ 6-fluoro-3- (4-methanesulfonylphenylsulfanyl) -2-methylindolizin-1-yl ] propionic acid, [ (ethanesulfonylaminobenzoyl) -6-fluoro-2-methylindolizin-1-yl ] acetic acid, [ 7-chloro-6-fluoro-3- (4-methanesulfonylphenylsulfanyl) -2-methylindol-1-yl ] acetic acid, [ 3- (2-chloro-4-methanesulfonylphenylsulfanyl) -7-cyano-2-methylindol-1-yl ] acetic acid, [ 6-cyano-3- (4-methanesulfonylbenzyl) -2-methylindol-1-yl ] acetic acid, [ 3- (4-chlorobenzyl) -7-cyano-2-methylindol-1-yl ] acetic acid, [ 6-cyano-3- (6-fluoroquinolin-2-ylmethyl) -2-methylindol-1-yl ] acetic acid, [ 6-fluoro-3- (4-methoxyphenylsulfanyl) -2-methylindol-1-yl ] acetic acid, [ 7-chloro-6-fluoro-3- (4-methoxyphenylsulfanyl) -2-methylindol-1-yl ] acetic acid, [ 3- (4-bromophenylsulfanyl) -6-fluoro-2-methylindolizin-1-yl ] acetic acid and [ 3- (4-cyclopropylsulfamoylphenylsulfanyl) -6-fluoro-2-methylindolizin-1-yl ] acetic acid.

Description

CRTH2 antagonists

technical field

The present invention relates to some specific neutral nitrogens that are ligands of CRTH2 receptor ( Chemoattractant Receptor-homologous molecule expressed on T H helper cells type 2 ) Indolizine compounds and their use in the treatment of diseases responsive to modulation of CRTH2 receptor activity, primarily diseases with a marked inflammatory response.

Background technique

Mast cells are known to play an important role in allergic and immune responses by releasing various regulators such as histamine, leukotrienes, cytokines, prostaglandin D2, etc. (Boyce; Allergy Asthma Proc., 2004, 25, 27-30). Prostaglandin D ₂ (PGD ₂ ) is the main metabolite of arachidonic acid released by mast cells in response to allergen challenge through the action of cyclooxygenase (Lewis et al; J. Immunol., 1982 , 129, 1627-1631). Increased production of _PGD2 has been shown in patients with systemic mastocytosis (Roberts; N. Engl. J. Med., 1980, 303, 1400-1404), allergic rhinitis (Naclerio et al. al; Am. Rev. Respir. Dis., 1983, 128, 597-602; Brown et al; Arch. Otolarynol. HeadNeck Surg., 1987, 113, 179-183; Lebel et al; J. Allergy Clin. Immunol. , 1988,82,869-877), bronchial asthma (Murray et al; N.Engl.J.Med., 1986,315,800-804; Liu et al; Am.Rev.Respir.Dis., 1990,142 , 126-132; Wenzel et al; J.Allergy Clin. Immunol., 1991, 87, 540-548), and urticaria (Heavey et al; J.Allergy Clin. Immunol., 1986, 78, 458-461) . PGD ₂ mediates effectors through two receptors, the PGD ₂ (or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916) and the chemotaxis expressed on Th2 Sex receptor-homologous molecule (or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278-1289; Powell; Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185). Therefore, it is hypothesized that agents that antagonize the effects of _PGD2 on its receptors may have beneficial effects on a variety of disease states.

The CRTH ₂ receptor has been shown to be expressed on cell types involved in allergic inflammation, such as basophils, eosinophils, and Th2-type immune helper cells (Hirai et al; J.Exp.Med., 2001, 193, 255-261). The CRTH2 receptor has been shown to regulate PGD ₂ -mediated cell migration in these cell types (Hirai et al; J. Exp. Med., 2001, 193, 255-261), and in a contact dermatitis model It plays a major role in the aggregation of neutrophils and eosinophils (Takeshita et al; Int. Immunol., 2004, 16, 947-959). It has been shown that ramatroban {(3R)-3-[(4-fluorophenyl)sulfonylamino]-1,2,3,4-tetrahydro-9H-carbazole-9-propionic acid} - a dual CRTH2 and thromboxane A ₂ (thromboxane A ₂ ) receptor antagonist - can attenuate the response (Sugimoto et al; J.Pharmacol.Exp.Ther., 2003, 305, 347-352; Takeshita et al ; the book cited above). The possibility of PGD ₂ both exacerbating allergic inflammation and inducing an inflammatory response has been demonstrated in mice and rats. Transgenic mice overexpressing _PGD2 synthase exhibit exacerbated pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen challenge (Fujitani et al, J. Immunol., 2002, 168, 443-449 ). In addition, exogenously administered CRTH2 agonists also enhanced allergic responses in sensitized mice (Spiket al; J. Immunol., 2005, 174, 3703-3708). Exogenous administration of CRTH2 agonists in rats resulted in pulmonary eosinophilia, whereas DP agonists (BW 245C) or TP agonists (I-BOP) showed no effect (Shirashi et al; J. Pharmacol. ExpTher. , 2005, 312, 954-960). These data suggest that CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by _PGD2 .

Our co-pending application PCT/GB2006/002341 relates to CRTH2 antagonist compounds of formula (I) and their salts, N-oxides, hydrates and solvates:

in

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, C ₁ -C ₆ alkyl, fully or partially fluorinated C ₁ -C ₆ alkyl, halogen, -S(O) _n R ₁₀ , -SO ₂ N(R ₁₀ ) ₂ , -N(R ₁₀ ) ₂ , -C(O)N(R ₁₀ ) ₂ , -NR ₁₀ C(O)R ₉ , -CO ₂ R ₁₀ , -C(O )R ₉ , -NO ₂ , -CN or -OR ₁₁ ;

Wherein each R ₉ is independently C ₁ -C ₆ alkyl, aryl, heteroaryl;

R ₁₀ is independently hydrogen, C ₁ -C ₆ alkyl, aryl or heteroaryl;

R ₁₁ is hydrogen, C ₁ -C ₆ alkyl, fully or partially fluorinated C ₁ -C ₆ alkyl or the group -SO ₂ R ₉ ;

n is 0, 1 or 2;

R ₅ is C ₁ -C ₆ alkyl, fully or partially fluorinated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, optionally substituted aryl or optionally Substituted heteroaryl;

R ₆ is hydrogen, C ₁ -C ₆ alkyl, or fully or partially fluorinated C ₁ -C ₆ alkyl;

R ₇ and R ₈ are independently hydrogen or C ₁ -C ₆ alkyl, or R ₇ and R ₈ together with the atoms to which they are attached form a cycloalkyl group; and

X is -CHR ₆ -, -S(O) _n -, -NR ₆ SO ₂ - or -SO ₂ NR ₆ -, wherein n is 0, 1 or 2,

With the proviso that if X is _-CH2- , _R6 is methyl and _R5 is 4-chlorophenyl, then _R1 , _R2 , _R3 , _R4 , _R7 and _R8 are not all hydrogen.

Detailed description of the invention

The present invention provides a group of specific compounds that fall within the scope of our co-pending application PCT/GB2006/002341 referred to above, but not specifically disclosed in that application.

The present invention provides compounds selected from the group consisting of:

[3-(2,4-Dichlorophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid,

[6-fluoro-3-(2-fluoro-4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid,

[6-fluoro-3-(4-methylsulfonyl-2-trifluoromethylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid,

(R) 2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propanoic acid,

(S) 2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propionic acid,

[3-(4-Ethylphenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid,

[(Ethylaminobenzenesulfonyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid,

[7-Chloro-6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid,

[3-(2-Chloro-4-methylsulfonylphenylsulfanyl)-7-cyano-2-methylindolizine-1-yl]acetic acid,

[6-cyano-3-(4-methylsulfonylbenzyl)-2-methylindolizine-1-yl]acetic acid,

[3-(4-Chlorobenzyl)-7-cyano-2-methylindolizine-1-yl]acetic acid,

[6-cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizine-1-yl]acetic acid,

[6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid,

[7-Chloro-6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid,

[3-(4-Bromophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid,

[3-(4-Cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid

and their salts, N-oxides, hydrates and solvates.

The compounds involved in the present invention are CRTH2 receptor antagonists.

A second aspect of the invention is a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable carrier or excipient.

A third aspect of the invention is a compound of the invention for therapeutic use.

The fourth aspect of the present invention is the use of the compound of the present invention in the preparation of a medicament for the treatment of a disease, wherein the CRTH2 antagonist can prevent, inhibit or improve the pathology and/or symptoms of the disease. Such diseases include: asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome or allergic rhinobronchitis, as well as atopic and non-atopic dermatitis, Crohn's disease, ulcerative colitis and irritable bowel disease.

A fifth aspect of the present invention is a method of treating a disease in a patient wherein a CRTH2 antagonist prevents, suppresses or ameliorates the pathology and/or symptoms of the disease, the method comprising administering to the patient a therapeutically effective Quantities of compounds of the invention.

Specifically, the compounds involved in the present invention can be used for the treatment of diseases associated with elevated levels of prostaglandin D2 (PGD2) or one or more active metabolites thereof.

Examples of such diseases include: asthma, rhinitis, allergic airway syndrome, allergic rhinobronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer's lung, fibrosis Pulmonary, cystic fibrosis, chronic cough, conjunctivitis, atopic and non-atopic dermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia syndrome, Huntington's disease, frontotemporal dementia, Lewy's disease dementia, vascular dementia, Guillain-Barr syndrome, chronic demyelinating polyneuropathy, multifocal motor neuropathy, plexus disease, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and cerebral Myelitis, CNS injury, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Behcet's disease, bursitis, carpal tunnel syndrome, inflammatory bowel disease, Crohn's disease, Ulcerative colitis, dermatomyositis, Ehlers-Danlos syndrome (EDS), fibromyalgia, myofascial pain, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Lytle's ) syndrome (reactive arthritis), sarcoidosis, scleroderma, xerostomia-rheumatoid arthritis syndrome, soft tissue disease, Still's disease, tendonitis, polyarteritis nodosa, Weber Garner's granulomatous disease, myositis (polymyositis-dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus (SLE), type 1 diabetes mellitus, nephritic syndrome, nephropathy Glomeronephritis, acute and chronic renal failure, eosinophilic fasciitis, hyper-IgE syndrome, sepsis, septic shock, myocardial ischemia-reperfusion, post-transplant allograft rejection, and graft-versus-host disease.

However, the compounds of the present invention are of major value in the treatment of asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome or allergic rhinobronchitis, and atopic and non-atopic dermatitis, clonal ( disease, ulcerative colitis, and irritable bowel disease.

The term "salt" as used herein includes base addition salts, acid addition salts and quaternary salts. The acidic compounds of the present invention may form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, hydroxide Barium and magnesium hydroxide; organic bases such as N-methyl-D-glucamine, choline tris(hydroxymethyl)aminomethane, L-arginine, L-lysine, N-ethylpiperidine , Dibenzylamine, etc. Specific salts with bases include those of benzathine penicillin G, calcium, diethanolamine, meglumine, ethanolamine, potassium, procaine, sodium, tromethamine and zinc. The basic compounds of the present invention can form salts, including pharmaceutically acceptable salts, with inorganic acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, etc.; and organic acids such as acetic acid, tartaric acid, succinic acid, etc. acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid and mandelic acid, etc.

The use of prodrugs, such as esters, of the compounds involved in the invention is also part of the invention. "Prodrug" means a compound that can be converted in vivo to a compound of formula (I) by metabolic means, for example by hydrolysis, reduction or oxidation. For example ester prodrugs of compounds of formula (I) can be converted in vivo to the parent molecule by hydrolysis. Suitable esters of compounds of formula (I) are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, Fumarate, maleate, methylene-di-beta-hydroxynaphthoate, gentisate, isethionate, di-toluoyl tartrate, mesylate , ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclamate and quinate. Examples of ester prodrugs are those described in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, references to compounds of formula (I) are also intended to include said prodrug forms.

combination

As stated above, the present invention relates to compounds which are CRTH2 receptor antagonists and are useful in the treatment of diseases which benefit from such modulation. Examples of such diseases are as described above and include asthma, rhinitis, allergic airway syndrome and allergic rhinobronchitis.

It is to be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, the patient's age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, The combination of medications and the severity of the particular disease being treated. Optimal dosage levels and dosing frequency will be determined through clinical trials in accordance with regulations in the field of medicine. Generally, the daily dosage range will be in the range of about 0.001 mg to about 100 mg per kg of mammalian body weight, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, administered in single or divided doses. On the other hand, it may be necessary to use an amount outside the above range in some cases.

The compounds involved in the present invention can be prepared in a form that can be administered by any route consistent with their pharmacokinetic properties. Oral compositions can be in the form of tablets, capsules, powders, granules, lozenges, liquids or gel preparations, such as solutions or suspensions for oral, external or sterile injection. Tablets and capsules for oral administration may be presented in unit-dose packaging and may contain conventional excipients, for example: binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl-pyrrolidone; Bulking agents such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide; disintegrants, such as potato starch; or an acceptable humectant such as sodium lauryl sulfate. The tablets may be coated according to methods well known in ordinary pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product requiring water or other suitable vehicle before use. agent recovery. The liquid preparations may contain conventional additives such as: suspending agents such as sorbitol, syrup, methylcellulose, glucose syrup, edible fat hydrogenated from gelatin; emulsifiers such as lecithin, sorbitan mono Oleate or gum arabic; non-aqueous excipients (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethanol; preservatives such as methylparaben or propylparaben or sorbic acid; and, if desired, conventional flavoring or coloring agents.

For topical application to the skin, the drug may be formulated as a cream, lotion or ointment. Cream or ointment formulations that can be used in medicine are conventional formulations well known in the art, for example, formulations recorded in standard pharmaceutical textbooks such as British Pharmacopoeia.

The medicament may also be formulated for use by inhalation, for example as a nasal spray, or as a dry powder or aerosol inhalation. For delivery by inhalation, the active compound is preferably in microparticulate form. They can be prepared by a variety of techniques including spray drying, freeze drying and micronization. Aerosols can be prepared using, for example, pressure-driven jet nebulizers or ultrasonic nebulizers, preferably using propellant-driven metered aerosols or propellant-free administration of e.g. from inhalation capsules or other "dry powder" delivery systems. Micronized active compound.

The active ingredient can also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Other compounds may be used in combination with the compounds of the present invention for the prevention and treatment of prostaglandin-mediated diseases. Accordingly, the present invention also relates to pharmaceutical compositions for the prevention and treatment of _PGD2 -mediated diseases comprising a therapeutically effective amount of a compound of the present invention and one or more other therapeutic agents. Therapeutic agents suitable for combination therapy with the compounds of the present invention include, but are not limited to: (1) cortisol, such as fluticasone, budesonide or ciclesonide; (2) beta2-adrenal (3) leukotriene modulators, for example, leukotriene antagonists such as montelus Montelukast or pranlukast, or leukotriene biosynthesis inhibitors such as Zileuton or BAY-x1005; (4) anticholinergics, for example, muscarinic-3 (M ₃ ) receptor antagonists such as tiotropium bromide (tiotropium bromide); (5) phosphodiesterase-IV (PDE-IV) inhibitors such as roflumilast (roflumilast) or cilomilast (cilomilast); ( 6) Antihistamines, for example, selective histamine-1 (H1) receptor antagonists, such as loratidine or astemizole; (7) Antitussives, such as codeine (codeine) or dextramorphan; (8) non-selective COX-1/COX-2 inhibitors such as ibuprofen or ketoprofen; (9) COX-2 inhibitors , such as celecoxib and rofecoxib; (10) VLA-4 antagonists, such as those described in WO97/03094 and WO97/02289; (11) TNF-α inhibitors, For example, anti-TNF monoclonal antibodies, such as Remicade (Remicade) and CDP-870, and TNF receptor immunoglobulin molecules, such as Enbrel; (12) matrix metalloproteinase (MMP) inhibitors, such as MMP8, 9 and 12; (13) human neutrophil elastase inhibitors, such as those described in WO2005/026124 and WO2003/053930; (14) vidarabine A2a agonists, such as those described in EP1052264 and EP1241176 (15) vidarabine A2b antagonists, such as those described in WO2002/42298; (16) modulators with chemokine receptor function, such as antagonists of CCR3 and CCR8; (17) modulation of other prostate (18) compounds that modulate Th2 function, such as PPAR agonists.

The weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dosage of each ingredient. Generally, effective doses of each will be used.

biological method

Compounds of the invention can be tested using the following biological assays to determine their ability to displace _PGD2 from the CRTH2 receptor and their ability to antagonize the functional role of _PGD2 on the CRTH2 receptor in a whole cell system.

Radioligand Binding Assay

Receptor binding assays were performed in a final volume of 200 μL of binding buffer [10 mM BES (pH 7.4), 1 mM EDTA, 10 mM manganese dichloride, 0.01% BSA)] and 1 nM [ ³ H]-PGD ₂ (Amersham Biosciences UK Ltd ) in. Ligands were added to assay buffer containing a constant amount of DMSO (1% by volume). Total binding was determined using 1 vol% DMSO in assay buffer and non-specific binding was determined using 10 μΜ unlabeled _PGD2 (Sigma). Human embryonic kidney (HEK) cell membranes (3.5 μg) expressing CRTH2 receptors were cultured with 1.5 mg wheat germ agglutinin SPA microbeads and 1 nM [ ³ H]-PGD ₂ (Amersham Biosciences UK Ltd), and the mixture was incubated at room temperature for 3 Hour. Bound [ ³ H]-PGD ₂ was determined using a Microbeta TRILUX liquid scintillation counter (Perkin Elmer). Compound _IC50 values were determined using 6-point dose response curves with semi-log compound dilution series obtained in duplicate. _IC50 was calculated using Excel and XLfit (Microsoft), and this value was used to determine the Ki value of the test compound according to the Cheng-Prusoff formula.

functional assay

Calcium mobilization (flux) test

Stable CHO-K1 cells co-expressing CRTH2 receptor and G-protein G α-16 were inoculated in (F-12Ham supplemented with 1% fetal bovine serum) 24 hours before the assay, the well volume was 75 μL, and 40,000 cells per well ) in a collagen-coated 96-well plate. Cells were then loaded with a fluorescence-imaging plate reader (FLI PR) calcium kit dye (Calcium 3 kit, MolecularDevices Ltd) containing probenecid at a final concentration of 5 mM and incubated at 5 mM. Incubate at 37°C for 1 hour in a %CO ₂ atmosphere. Fluorescence emission through _PGD2- induced intracellular calcium mobilization at the CRTH2 receptor was determined using a FLEXstation benchtop scanning and integrated fluid transfer workstation (Molecular Devices Ltd). To detect antagonists and determine the _IC50 of the compounds, various concentrations of the compounds were pre-incubated with the loaded cells at 37°C for 15 minutes in a 5% _CO2 atmosphere before the addition of the agonists with _EC80 values. Compounds and agonists were added as Hanks balanced salt solution containing 20 mM HEPES and 0.1% BSA. Partial response values for each well were calculated by subtracting the base response from the peak response. The average of triplicate wells was calculated using Excel and XLfit (Microsoft) as the result.

The following examples describe the preparation of compounds of the invention:

Example

¹ H NMR spectra were recorded at room temperature on a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations are used: brs = broad singlet, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet.

Mass spectrometry (LCMS) experiments were performed using the following method to determine retention times and associated mass ions:

Method A: Experiments were performed on a MicromassPlatform LCT spectrometer with positive ion electrospray and single-wavelength UV 254nm detection using a Higgins Clipeus C18 5μm 100×3.0mm column and a flow rate of 2mL/min. The initial solvent system for the first minute was 95% water with 0.1% formic acid (solvent A) and 5% acetonitrile with 0.1% formic acid (solvent B), followed by a 14-minute gradient to 5% solvent A and 95% solvent B. The final solvent system was held constant for an additional 2 minutes.

Method B: Experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/diode array detection using a Phenomenex Luna C18(2) 30×4.6 mm column and a flow rate of 2 mL/min. The solvent system was 95% solvent A and 5% solvent B for the first 0.50 minutes followed by a gradient to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for an additional 0.50 minutes.

Microwave experiments were performed using a Personal Chemistry Smith Synthesizer ^™ , which employs single-mode resonators and dynamic field tuning techniques, both of which make them reproducible and controllable. The temperature can reach 40-250°C, and the pressure can reach up to 20bar. Two types of vials are available for this processor, 0.5-2.0 mL and 2.0-5.0 mL.

Reverse-phase preparative HPLC purification was performed using a Genesis 7 micron C-18 bonded silica stationary phase in a 10 cm long, 2 cm internal diameter column. The mobile phase used was a mixture of acetonitrile and water (both buffered with 0.1% v/v trifluoroacetic acid) at a flow rate of 10 mL per minute and a conventional gradient of 40% organic modifier to 90% over 30 to 40 minutes. % organic modifier. Fractions containing the desired product (identified by LC-MS analysis) were pooled, the organic fraction was removed by evaporation, and the remaining aqueous fraction was lyophilized to yield the final product.

Example 1: [3-(2,4-dichlorophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid

Preparation 1a: Ethyl 3-(5-fluoropyridin-2-yl)propanoate

A solution of 3-ethoxy-3-oxopropylzinc bromide in tetrahydrofuran (0.5M, 630 mL) was added dropwise to 2-bromo-5-fluoropyridine (50 g), tetrakis(triphenylphosphine) at room temperature In a mixture of palladium(0) (5.5g) and toluene (350mL). The resulting mixture was stirred at room temperature for 24 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate and filtered through diatomaceous earth (hyflo), and the filtrate was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of pentane and ethyl acetate (9:1 by volume) to obtain 35 g of the title compound as a yellow oil.

¹ H NMR (CDCl ₃ ): δ1.25(t, J=7.1Hz, 3H), 2.75(t, J=7.4Hz, 2H), 3.10(t, J=7.4Hz, 2H), 4.10(q, J = 7.1 Hz, 2H), 7.20 (dd, J = 4.4, 8.4 Hz, 1H), 7.30 (dt, J = 3.0, 8.4 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H).

Preparation 1b: Ethyl (6-fluoro-2-methylindolizin-1-yl)acetate

A mixture of ethyl 3-(5-fluoropyridin-2-yl)propanoate (12 g) and acetonitrile (90 mL) was treated with a solution of 1-bromopropan-2-one (16 g) in acetonitrile (30 mL) at room temperature, The resulting mixture was heated to reflux for 24 hours and then left at room temperature for 60 hours. The mixture was treated with pyridine (35 mL), and the resulting mixture was heated to reflux for 4 hours, cooled to room temperature, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of pentane and ethyl acetate (19:1 by volume) to afford 3.7 g of the title compound as a yellow oil.

¹ H NMR (CDCl ₃ ): δ1.25(t, J=7.1Hz, 3H), 2.25(s, 3H), 3.65(s, 2H), 4.11(q, J=7.1Hz, 2H), 6.55( m, 1H), 7.10 (brs, 1H), 7.25 (m, 1H), 7.70 (d, J = 3.4 Hz, 1H).

Preparation 1c: Ethyl [3-(2,4-dichlorophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate

A mixture of ethyl (6-fluoro-2-methylindolizine-1-yl)acetate (0.10 g) and toluene (20 mL) was treated with 2,4-dichlorobenzenesulfonyl chloride (0.16 g) and aluminum chloride (0.010 g) was treated and the resulting mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with a mixture of ethyl acetate and water. The resulting mixture was filtered through celite, and the organic filtrate was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of pentane and ethyl acetate (19:1 by volume) to obtain 0.052 g of the title compound as a light brown oil.

¹ H NMR (CDCl ₃ ): δ1.25(t, J=7.1Hz, 3H), 2.35(s, 3H), 3.75(s, 2H), 4.15(q, J=7.1Hz, 2H) 6.00(d , J=8.5Hz, 1H), 6.80(m, 1H), 6.90(d, J=2.1Hz, 1H), 7.35(d, J=2.1Hz, 1H), 7.40(dd, J=5.2, 9.7Hz , 1H), 8.00 (dd, J=2.1, 5.2 Hz, 1H).

Preparation 1d: [3-(2,4-Dichlorophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

A mixture of ethyl [3-(2,4-dichlorophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate (0.052 g) and methanol (2.0 mL) was Aqueous 1.0M lithium hydroxide was treated and the resulting compound was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water, and acidified by adding 1.0M aqueous hydrochloric acid. The mixture was extracted with dichloromethane, the combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC eluting with a gradient of acetonitrile in water (organic modifier from 70% to 95%) over 30 minutes to afford 0.032 g of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ2.35(s, 3H), 3.80(s, 2H), 6.00(d, J=8.5Hz, 1H), 6.80(m, 1H), 6.90(dd, J=2.1 , 8.5Hz, 1H), 7.35 (d, J = 1.9Hz, 1H), 7.40 (m, 1H), 8.00 (dd, J = 1.9, 5.0Hz, 1H).

MS: ESI (+ve) (method A): 384 (M+H) ⁺ , retention time 14.0 min.

Example 2: [6-fluoro-3-(2-fluoro-4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

Preparation 2a: 1,2-Difluoro-4-methanesulfonylbenzene

3-Chloroperoxybenzoic acid (19 g) was added in portions at room temperature to a solution of 1,2-difluoro-4-methylsulfanylbenzene (5.4 g) in dichloromethane (100 mL), and the resulting mixture Stir overnight at room temperature. The mixture was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford 5.5 g of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 3.05 (s, 3H), 7.40 (m, 1H), 7.75-7.85 (m, 2H).

Preparation 2b: Bis(2-fluoro-4-methanesulfonylphenyl)disulfide

A mixture of 1,2-difluoro-4-methanesulfonylbenzene (2.8 g), sodium hydrosulfide (11 g) and 1-methylpyrrolidin-2-one (30 mL) was stirred at 80° C. for 90 minutes, and then Stir overnight at room temperature. The mixture was diluted with water (40 mL), acidified by the addition of concentrated hydrochloric acid, and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from toluene to give 1.4 g of the title compound as cream crystals.

MS: ESI (+ve) (method B): 411 (M+H) ⁺ , retention time 3.1 min.

Preparation 2c: Ethyl [6-fluoro-3-(2-fluoro-4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate

Sulfuryl chloride (0.066 mL) was added to a mixture of bis(2-fluoro-4-methanesulfonylphenyl) disulfide (0.39 g) and dichloroethane (5.0 mL) at 0° C., and the resulting mixture was incubated at room temperature Stir for 30 minutes. A solution of ethyl (6-fluoro-2-methylindolizine-1-yl)acetate (0.15 g) in dichloroethane (5.0 mL) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of toluene, dichloromethane and ethyl acetate (volume ratio 1:4:0 to 0:1:0 and then to 0:9:1) , yielding 0.25 g of the title compound as a yellow solid.

MS: ESI (+ve) (method B): 440 (M+H) ⁺ , retention time 4.1 min.

Preparation 2d: Ethyl [6-fluoro-3-(2-fluoro-4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate

[6-Fluoro-3-(2-fluoro-4-methanesulfonylsulfanyl)-2-methylindolizine-1-yl]ethyl acetate (0.25g), tetrahydrofuran (3.0mL) A mixture of this and 1.0 M aqueous lithium hydroxide solution (3.0 mL) was stirred at room temperature for 3 hours. The tetrahydrofuran was removed under reduced pressure, and the pH of the residue was adjusted to 4 by adding sodium dihydrogen phosphate. The resulting precipitate was collected by filtration to afford 0.22 g of the title compound.

¹ H NMR (DMSO-d6): 2.25(s, 3H), 3.20(s, 3H), 3.70(s, 2H), 6.40(dd, J=7.5, 8.1Hz, 1H), 7.00(m, 1H) , 7.55(dd, J=1.8, 8.3Hz, 1H), 7.70(dd, J=5.5, 9.8Hz, 1H), 7.85(dd, J=1.8, 7.5Hz, 1H), 8.35(dd, J=2.1 , 5.5Hz, 1H).

MS: ESI (+ve) (method A): 412 (M+H) ⁺ , retention time 10.2 min.

Example 3: [6-fluoro-3-(4-methylsulfonyl-2-trifluoromethylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

Preparation 3a: 1-Fluoro-4-methylsulfanyl-2-trifluoromethylbenzene

A mixture of dimethyl disulfide (2.0 mL), 4-fluoro-3-trifluoromethylaniline (2.0 g) and acetonitrile (50 mL) at room temperature was treated dropwise with isoamyl nitrite (2.0 mL) , and the resulting mixture was stirred at 60 °C for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 0.67 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 2.50 (s, 3H), 7.15 (m, 1H), 7.40-7.50 (m, 2H).

Preparation 3b: 1-Fluoro-4-methanesulfonyl-2-trifluoromethylbenzene

3-Chloroperoxybenzoic acid (2.4g) was added in portions at room temperature to a solution of 1-fluoro-4-methylsulfanyl-2-trifluoromethylbenzene (1.3g) in dichloromethane (50mL) , and the resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then filtered over magnesium sulfate. The solvent was removed under reduced pressure to afford 1.5 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 3.1 (s, 3H), 7.45 (t, J=9.3Hz, 1H), 8.20 (m, 1H), 8.25 (m, 1H).

Preparation 3c: Bis(2-trifluoromethyl-4-methanesulfonylphenyl)disulfide

A mixture of 1-fluoro-4-methanesulfonyl-2-trifluoromethylbenzene (1.4g), sodium hydrosulfide (4.6g) and 1-methylpyrrolidin-2-one (6.0mL) was heated at 80°C Stir for 2 hours, then overnight at room temperature. The mixture was diluted with water, washed with ethyl acetate, and the aqueous phase was acidified by adding concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, the combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated with ethyl acetate to give 0.94 g of the title compound.

Preparation 3d: Ethyl [6-fluoro-3-(2-trifluoromethyl-4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate

Sulfuryl chloride (0.060 mL) was added to a mixture of bis(2-trifluoromethyl-4-methanesulfonylphenyl) disulfide (0.45 g) and dichloroethane (10 mL) at 0 ° C, and the resulting mixture Stir at room temperature for 30 minutes, then at 60°C for 4 hours. A solution of ethyl (6-fluoro-2-methylindolizin-1-yl)acetate (0.15 g) in dichloroethane (5.0 mL) was added, and the resulting mixture was stirred at 60°C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane, dichloromethane and ethyl acetate (1:4:0 to 0:19:1 by volume). Further purification by preparative reverse phase HPLC gradient elution with acetonitrile in water (organic modifier from 50% to 98%) over 20 minutes afforded 0.030 g of the title compound as a yellow solid.

MS: ESI (+ve) (method B): 490 (M+H) ⁺ , retention time 4.3 min.

Preparation 3e: [6-Fluoro-3-(4-methanesulfonyl-2-trifluoromethylphenylsulfanyl)-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 2d using ethyl [6-fluoro-3-(2-fluoro-4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate.

¹ H NMR (DMSO-d6): δ2.25(s, 3H), 3.25(s, 3H), 3.80(s, 2H), 6.50(d, J=8.5Hz, 1H), 7.10(m, 1H) , 7.70(dd, J=5.5, 9.8Hz, 1H), 7.90(dd, J=1.9, 8.4Hz, 1H), 8.20(d, J=1.9Hz, 1H), 8.20(m, 1H), 12.20( br s, 1H).

MS: ESI (+ve) (method A): 462 (M+H) ⁺ , retention time 11.1 min.

Example 4: (R)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propionic acid

Preparation 4a: (R)-3-(5-Fluoropyridin-2-yl)-2-methylpropanoic acid methyl ester

A solution of (S)-3-methoxy-2-methyl-3-oxopropylzinc bromide in tetrahydrofuran (0.5M, 20mL) was added dropwise to 2-bromo-5-fluoropyridine (1.0 g), in a mixture of tetrakis(triphenylphosphine)palladium(0) (0.14g) and toluene (20mL). The resulting mixture was stirred at room temperature for 6 hours, then at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was diluted with a mixture of ethyl acetate and water. The mixture was filtered through celite, washed with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of pentane and ethyl acetate (9:1 by volume) to obtain 0.87 g of the title compound.

¹ H NMR (CDCl ₃ ): δ1.20(d, J=7.0Hz, 3H), 2.85(dd, J=6.6, 13.7Hz, 1H), 3.00(m, 1H), 3.20(dd, J=7.6 , 13.7Hz, 1H), 3.65(s, 3H), 7.15(dd, J=4.4, 8.5Hz, 1H), 7.30(dt, J=2.9, 8.5Hz, 1H), 8.40(d, J=2.9Hz , 1H).

Preparation 4b: (R)-methyl 2-(6-fluoro-2-methylindolizin-1-yl)propanoate

The title compound was prepared by the method of Preparation 1b using (R)-3-(5-fluoropyridin-2-yl)-2-methylpropanoic acid methyl ester.

MS: ESI (+ve) (method B): 236 (M+H) ⁺ , retention time 3.7 min.

Preparation 4c: Bis[4-(methylsulfonyl)phenyl]disulfide

A mixture of 1-fluoro-4-methanesulfonylbenzene (32 g), sodium hydrosulfide (64 g) and 1-methylpyrrolidin-2-one (100 mL) was stirred at 80° C. for 60 minutes, then at room temperature for 60 minutes . The mixture was diluted with water, filtered, and the filtrate acidified by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give 15 g of the title compound as a white solid.

MS: ESI (+ve) (method B): 375 (M+H) ⁺ , retention time 3.3 min.

Preparation 4d: (R)-Methyl 2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]propanoate

The title compound was prepared by the method of Preparation 2c using (R)-methyl 3-(5-fluoropyridin-2-yl)-2-methylpropanoate and bis[4-(methylsulfonyl)phenyl]disulfide preparation.

MS: ESI (+ve) (method B): 422 (M+H) ⁺ , retention time 4.0 min.

Preparation 4e: (R)-2-[6-Fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]propanoic acid

The title compound was prepared from (R)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]propanoic acid methyl ester by preparation of 1d Method preparation.

¹ H NMR (CDCl ₃ ): δ1.60 (d, J = 7.1 Hz, 3H), 2.35 (s, 3H), 3.00 (s, 3H), 4.10 (q, J = 7.1 Hz, 1H), 6.80 ( m, 1H), 6.90 (d, J=8.6Hz, 2H), 7.50 (dd, J=5.3, 9.7Hz, 1H), 7.70 (d, J=8.6Hz, 2H), 8.00 (m, 1H).

MS: ESI (+ve) (method A): 408 (M+H) ⁺ , retention time 10.4 min.

Example 5: [3-(4-Ethylsulfonylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid

Preparation 5a: 1-Ethylsulfanyl-4-fluorobenzene

A mixture of diethyldisulfide (11 mL), 4-fluoroaniline (5.0 g) and dichloromethane (50 mL) was treated dropwise with tert-butyl nitrite (7.7 mL) at room temperature, and the resulting mixture was Stir at 50°C for 5 minutes, then at room temperature for 3 hours. The mixture was washed with water and 1.0M aqueous hydrochloric acid, then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with cyclohexane to obtain 3.5 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.25 (t, J = 7.3 Hz, 3H), 2.90 (q, J = 7.3 Hz, 2H), 7.00 (m, 2H), 7.35 (m, 2H).

Preparation 5b: 1-Ethylsulfonyl-4-fluorobenzene

A solution of 1-ethylsulfanyl-4-fluorobenzene (3.5 g) in dichloromethane (20 mL) was treated with 3-chloroperoxybenzoic acid (6.0 g) at room temperature, and the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 4.3 g of the title compound.

¹ H NMR (DMSO-d6): δ 1.10 (t, J = 7.3 Hz, 3H), 3.30 (q, J = 7.3 Hz, 2H), 7.50 (m, 2H), 8.00 (m, 2H).

Preparation 5c: Bis(4-ethylsulfonylphenyl)disulfide

A mixture of 1-ethanesulfonyl-4-fluorobenzene (1.0 g), sodium hydrosulfide (4.4 g) and 1-methylpyrrolidin-2-one (4.0 mL) was stirred at 80° C. for 2 hours, then at room temperature Stir overnight. The mixture was diluted with water, washed with ethyl acetate, and the aqueous phase was acidified by adding 1.0M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, the combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 0.80 g of the title compound.

¹ H NMR (DMSO-d6): δ1.10 (t, J=7.4Hz, 6H), 3.30 (q, J=7.4Hz, 4H), 7.80-7.90 (m, 8H).

Preparation 5d: Ethyl [3-(4-ethylsulfonylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 2c using ethyl (6-fluoro-2-methylindolizin-1-yl)acetate and bis(4-ethylsulfonylbenzene)disulfide.

MS: ESI (+ve) (method B): 436 (M+H) ⁺ , retention time 4.1 min.

Preparation 5e: [3-(4-Ethylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

A solution of ethyl [3-(4-ethylsulfonylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate (0.14 g) in tetrahydrofuran (6.0 mL) was oxidized with hydrogen A solution of lithium (0.040 g) in water (6.0 mL) was treated and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0M aqueous hydrochloric acid, extracted with ethyl acetate, and the combined extracts were concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC eluting with a gradient of acetonitrile in water to afford 0.020 g of the title compound as a green solid.

¹ H NMR (CD ₃ OD): δ1.15(t, J=7.5Hz, 3H), 2.30(s, 3H), 3.10(q, J=7.5Hz, 2H), 3.75(s, 2H), 6.85 (m, 1H), 7.00(d, J=8.7Hz, 2H), 7.55(m, 1H), 7.70(d, J=8.7Hz, 2H), 8.10(dd, J=2.1, 5.4Hz, 1H) .

MS: ESI (+ve) (method A): 435 (M+H) ⁺ , retention time 10.2 min.

Example 6: (S)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propanoic acid

Preparation 6a: (S)-Methyl 3-(5-fluoropyridin-2-yl)-2-methylpropanoate

The title compound was prepared by the method of Preparation 4a using (R)-3-methoxy-2-methyl-3-oxopropylzinc bromide and 2-bromo-5-fluoropyridine.

MS: ESI (+ve) (method B): 198 (M+H) ⁺ , retention time 2.6 min.

Preparation 6b: (S)-methyl 2-(6-fluoro-2-methylindolizin-1-yl)propanoate

The title compound was prepared by the method of Preparation 1b using (S)-methyl 3-(5-fluoropyridin-2-yl)-2-methylpropanoate.

MS: ESI (+ve) (method B): 236 (M+H) ⁺ , retention time 3.7 min.

Preparation 6c: (S)-methyl 2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]propanoate

The title compound was prepared using (S)-methyl 2-(6-fluoro-2-methylindolizin-1-yl)propionate and bis[4-(methylsulfonyl)phenyl]disulfide via Preparation 2c method of preparation.

MS: ESI (+ve) (method B): 422 (M+H) ⁺ , retention time 4.0 min.

Preparation 6d: (S)-Methyl 2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]propanoate

Methyl (S)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propionate (0.25 g), methanol ( 10 mL) and 1.0 M aqueous lithium hydroxide solution (3.0 mL) was stirred at 65°C for 8 hours. The mixture was concentrated under reduced pressure, diluted with water, and washed with dichloromethane. The aqueous phase was acidified by addition of glacial acetic acid, extracted with dichloromethane, and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of acetonitrile (organic modifier from 50% to 98%) in water over 30 minutes to afford 0.17 g of the title compound as a light green solid.

¹ H NMR (CDCl ₃ ): δ1.60 (d, J = 7.4Hz, 3H), 2.35 (s, 3H), 3.00 (s, 3H), 4.05 (q, J = 7.4Hz, 1H), 6.75 ( m, 1H), 6.90(d, J=8.6Hz, 2H), 7.50(dd, J=5.3, 9.7Hz, 1H), 7.70(d, J=8.6Hz, 2H), 8.80(dd, J=2.0 , 4.5Hz, 1H).

MS: ESI (+ve) (method A): 408 (M+H) ⁺ , retention time 10.6 min.

Example 7: [(Ethylaminobenzenesulfonyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

Preparation 7a: Ethyl[4-(4-Ethylaminophenyldisulfanyl)phenyl]amine

A solution of ethanesulfonyl chloride (1.9 mL) in dichloromethane (5.0 mL) was added dropwise to a solution of 4-aminophenyl disulfide (2.0 g) and triethylamine (4.5 mL) in dichloromethane ( 20 mL) solution, and the resulting mixture was allowed to warm to room temperature over 4 hours. The mixture was washed with 1.0M aqueous sodium hydroxide, and the aqueous phase was acidified by adding 1.0M aqueous hydrochloric acid, then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 2.0 g of the title compound as a white solid.

¹ H NMR (DMSO-d6): δ1.15(t, J=7.4Hz, 6H), 3.10(q, J=7.4Hz, 4H), 7.20(m, 4H), 7.45(m, 4H), 9.85 (br s, 2H).

Preparation 7b: [3-(4-Ethylaminophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate ethyl ester

The title compound was passed through ethyl (6-fluoro-2-methylindolizine-1-yl)acetate and ethylsulfonyl[4-(4-ethylsulfonylaminophenyldisulfanyl)phenyl]amine Prepared by the method of Preparation 2c.

¹ H NMR (CDCl ₃ ): δ1.25(t, J=7.2Hz, 3H), 1.35(t, J=7.2Hz, 3H), 2.35(s, 3H), 3.05(q, J=7.2Hz, 2H), 3.75(s, 2H), 4.15(q, J=7.2Hz, 2H), 6.25(s, 1H), 6.75(m, 1H), 6.80(d, J=8.7Hz, 2H), 7.05( d, J=8.7Hz, 2H), 7.40 (dd, J=5.1, 9.8Hz, 1H), 8.1 (dd, J=2.1, 5.1Hz, 1H).

Preparation 7c: Methyl [3-(4-ethanesulfonamidobenzenesulfonyl)-6-fluoro-2-methylindolizin-1-yl]acetate

[3-(4-Ethylaminophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]ethyl acetate (0.030 g), 3-chloroperoxybenzoic acid ( 0.090 g), potassium carbonate (0.092 g) and methanol was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with water, and extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure to give the title compound.

MS: ESI (+ve) (method B): 469 (M+H) ⁺ , retention time 3.3 min.

Preparation 7d: [(Ethylaminobenzenesulfonyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [3-(4-ethanesulfonylaminobenzenesulfonyl)-6-fluoro-2-methylindolizin-1-yl]acetate.

MS: ESI (+ve) (method A): 455 (M+H) ⁺ , retention time 9.1 min.

MS: ESI (+ve) (method B): 455 (M+H) ⁺ , retention time 3.1 min.

Example 8: [7-Chloro-6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

Preparation 8a: Ethyl [7-chloro-6-fluoro-3-(4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate

Sulfuryl chloride (0.40 mL) was added to a mixture of bis[4-(methylsulfonyl)phenyl]disulfide (1.6 g) and dichloromethane (40 mL) at 0°C, and the resulting mixture was stirred at 0°C 10 minutes, then stirred at room temperature for 90 minutes. A solution of ethyl (6-fluoro-2-methylindolizine-1-yl)acetate (1.0 g) in dichloroethane (5.0 mL) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane and ethyl acetate (9:1 to 85:15 by volume) to give the title compound.

MS: ESI (+ve) (method B): 456 (M+H) ⁺ , retention time 4.3 min.

Preparation 8b: [7-Chloro-6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [7-chloro-6-fluoro-3-(4-methanesulfonylphenylsulfanyl)-2-methylindolizin-1-yl]acetate.

¹ H NMR (CDCl ₃ ): δ2.30(s, 3H), 3.00(s, 3H), 3.75(s, 2H), 6.90(d, J=8.6Hz, 2H), 7.45(d, J=7.0 Hz, 1H), 7.70 (d, J=8.6Hz, 2H), 8.05 (d, J=4.8Hz, 1H).

MS: ESI (+ve) (method A): 428 (M+H) ⁺ , retention time 11.8 min.

MS: ESI (+ve) (method B): 428 (M+H) ⁺ , retention time 3.6 min.

Example 9: [3-(2-Chloro-4-methylsulfonylphenylsulfanyl)-7-cyano-2-methylindolizine-1-yl]acetic acid

Preparation 9a: 2-Chloro-1-fluoro-4-methanesulfonylbenzene

A solution of sodium nitrite (5.7 g) in water (15 mL) was added dropwise to 2-fluoro-5-methanesulfonylphenylamine (15 g), concentrated hydrochloric acid (30 mL) and water at 0-10 °C over 15 minutes (90mL) mixture. The resulting solution was added to a mixture of cuprous(I) chloride (11.8 g) and concentrated hydrochloric acid (30 mL) at 0°C, and the resulting mixture was heated at 40°C for 10 minutes. The mixture was cooled to room temperature, filtered, and the filtrate was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of toluene, dichloromethane and ethyl acetate (volume ratio 2:1:0 to 0:1:0 to 0:50:1) to obtain 3.7 g of Title compound.

¹ H NMR (CDCl ₃ ): δ 3.05 (s, 3H), 7.35 (t, J=8.4Hz, 1H), 7.85 (m, 1H), 8.05 (dd, J=2.2, 6.6Hz, 1H).

Preparation 9b: Bis(2-chloro-4-methanesulfonylbenzene) disulfide

A mixture of 2-chloro-1-fluoro-4-methanesulfonylbenzene (1.0 g), sodium hydrosulfide (3.6 g) and 1-methylpyrrolidin-2-one (5.0 mL) was stirred at 80° C. for 90 minutes , and then stirred at room temperature for 4 hours. The mixture was diluted with water (40 mL) and acidified by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ethanol, then crystallized from toluene to give 0.61 g of the title compound as a white solid.

¹ H NMR (DMSO-d6): δ3.30 (s, 6H), 7.80 (d, J = 8.3Hz, 2H), 7.90 (dd, J = 1.5, 8.3Hz, 2H), 8.10 (br s, 2H ).

MS: ESI (+ve) (method B): 443 (M+H) ⁺ , retention time 3.8 min.

Preparation 9c: Ethyl [3-(2-chloro-4-methanesulfonylphenylsulfanyl)-7-cyano-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 2c using ethyl (7-cyano-2-methylindolizine-1-yl)acetate and bis(2-chloro-4-methanesulfonylbenzene)disulfide.

MS: ESI (+ve) (method B): 463 (M+H) ⁺ , retention time 3.7 min.

Preparation 9d: [3-(2-Chloro-4-methanesulfonylphenylsulfanyl)-7-cyano-2-methylindolizin-1-yl]acetic acid

Ethyl [3-(2-chloro-4-methylsulfonylphenylsulfanyl)-7-cyano-2-methylindolizin-1-yl]acetate (0.027g), 5.0M Hydroxide A mixture of aqueous lithium solution (0.25 mL), water (0.5 mL) and ethanol (5.0 mL) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue was partitioned between water (5.0 mL) and ethyl acetate (10 mL). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by preparative reverse phase HPLC gradient elution with acetonitrile (organic modifier from 45% to 95%) in water over 30 minutes to afford 0.019 g of the title compound.

¹ H NMR (DMSO-d6): δ2.20(s, 3H), 3.15(s, 3H), 3.80(s, 2H), 6.15(d, J=8.6Hz, 1H), 6.85(dd, J= 1.6, 7.1Hz, 1H), 7.55(dd, J=1.9, 8.4Hz, 1H), 8.00(d, J=1.9Hz, 1H), 8.20(dd, J=0.9, 7.1Hz, 1H), 8.35( dd, J = 0.9, 1.6 Hz, 1H).

MS: ESI (+ve) (method A): 435 (M+H) ⁺ , retention time 10.7 min.

Example 10: [6-cyano-3-(4-methylsulfonylbenzyl)-2-methylindolizine-1-yl]acetic acid

Preparation 10a: Ethyl 3-(5-cyanopyridin-2-yl)propanoate

3-Ethoxy-3-oxopropylzinc bromide in tetrahydrofuran (0.5M, 60mL) was added dropwise to 6-bromonicotinonitrile (5.0g), tetrakis(triphenyl phosphine) palladium(0) (0.69 g) and tetrahydrofuran (20 mL), and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (150 mL), basified by the addition of saturated aqueous sodium bicarbonate, and extracted with methyl tert-butyl ether. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of pentane, dichloromethane and ethyl acetate (volume ratio 2:1:0, 0:1:0 and 0:5:1) to give 4.1 g as light yellow Title compound as an oil.

¹ H NMR (CDCl ₃ ): δ1.25(m, 3H), 2.85(t, J=7.2Hz, 2H), 3.2(t, J=7.2Hz, 2H), 4.15(m, 2H), 7.35( d, J = 8.0 Hz, 1H), 7.85 (m, 1H), 8.80 (s, 1H).

MS: ESI (+ve) (method B): 205 (M+H) ⁺ , retention time 2.7 min.

Preparation 10b: Ethyl (6-cyano-2-methylindolizine-1-yl)acetate

A mixture of ethyl 3-(5-cyanopyridin-2-yl)propionate (3.2 g), 1-bromopropan-2-one (5.3 gmL), sodium bicarbonate (3.9 g) and acetonitrile (40 mL) Heat to reflux for 41 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of dichloromethane and pentane (1:4 to 1:1 by volume) to afford 0.51 g of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ): δ1.25(t, J=7.1Hz, 3H), 2.30(s, 3H), 3.65(s, 2H), 4.10(q, J=7.1Hz, 2H), 6.65( dd, J = 1.4, 9.3 Hz, 1H), 7.20 (m, 1H), 7.35 (dd, J = 0.9, 9.3 Hz, 1H), 8.20 (m, 1H).

MS: ESI (+ve) (method B): 443 (M+H) ⁺ , retention time 3.5 min.

Preparation 10c: Ethyl [6-cyano-3-(4-methanesulfonylbenzyl)-2-methylindolizin-1-yl]acetate

Ethyl (6-cyano-2-methylindolizine-1-yl)acetate (0.50g), 4-methylsulfonylbenzaldehyde (0.38g) and 1,2-dichloroethane (10mL) The mixture was treated dropwise with triethylsilane (1.6 mL) followed by trifluoroacetic acid (0.46 mL) at 0°C, and the resulting mixture was stirred at 0°C for 10 min and then at room temperature overnight. The mixture was diluted with 1,2-dichloroethane (10 mL), washed with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to obtain 0.43 g of the title compound as a beige solid.

MS: ESI (+ve) (method B): 411 (M+H) ⁺ , retention time 3.3 min.

Preparation 10d: [6-Cyano-3-(4-methanesulfonylbenzyl)-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [6-cyano-3-(4-methanesulfonylbenzyl)-2-methylindolizin-1-yl]acetate.

¹ H NMR (DMSO-d6): δ2.30(s, 3H), 3.00(s, 3H), 3.75(s, 2H), 4.30(s, 2H), 6.70(dd, J=1.0, 9.3Hz, 1H), 7.15(d, J=8.5Hz, 2H), 7.35(dd, J=1.0, 9.3Hz, 1H), 7.85(m, 3H).

MS: ESI (+ve) (method A): 383 (M+H) ⁺ , retention time 8.8 min.

Example 11: [3-(4-Chlorobenzyl)-7-cyano-2-methylindolizine-1-yl]acetic acid

Preparation 11a: Ethyl 3-(4-cyanopyridin-2-yl)propanoate

A solution of 3-ethoxy-3-oxopropylzinc bromide in tetrahydrofuran (0.5M, 8.0mL) was added dropwise at room temperature to 2-chloroisonicotinonitrile (0.50g), tetrakis(triphenylphosphine) palladium(0) (0.21 g) and toluene (8.0 mL), and the resulting mixture was stirred at 100° C. for 18 hr. The mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane and ethyl acetate (9:1 by volume) to obtain 0.44 g of the title compound.

MS: ESI (+ve) (method B): 205 (M+H) ⁺ , retention time 2.8 min.

Preparation 14b: Ethyl (7-cyano-2-methylindolizine-1-yl)acetate

A solution of ethyl 3-(4-cyanopyridin-2-yl)propionate (0.78g), 1-bromopropan-2-one (1.3g), sodium bicarbonate (0.96g) and acetonitrile (6.0mL) The mixture was sealed in a flask and heated at 110°C for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane and ethyl acetate (19:1 by volume) to obtain 0.29 g of the title compound.

MS: ESI (+ve) (method B): 243 (M+H) ⁺ , retention time 3.6 min.

Preparation 11c: Ethyl [3-(4-chlorobenzyl)-7-cyano-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 10c using ethyl (7-cyano-2-methylindolizin-1-yl)acetate and 4-chlorobenzaldehyde.

MS: ESI (+ve) (method B): 367 (M+H) ⁺ , retention time 4.3 min.

Preparation 11d: [3-(4-Chlorobenzyl)-7-cyano-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [3-(4-chlorobenzyl)-7-cyano-2-methylindolizin-1-yl]acetate.

¹ H NMR (CDCl ₃ ): δ2.30(s, 3H), 3.00(s, 3H), 3.75(s, 2H), 4.30(s, 2H), 6.70(dd, J=1.3, 9.3Hz, 1H ), 7.15 (d, J=8.5Hz, 2H), 7.35 (dd, J=0.8, 9.3Hz, 1H), 7.80 (m, 3H).

MS: ESI (+ve) (method A): 339 (M+H) ⁺ , retention time 11.2 min.

Example 12: [6-cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizine-1-yl]acetic acid

Preparation 12a: Ethyl [6-cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 10c using ethyl (6-cyano-2-methylindolizin-1-yl)acetate and 6-fluoroquinoline-2-carbaldehyde.

MS: ESI (+ve) (method B): 402 (M+H) ⁺ , retention time 4.0 min.

Preparation 12b: [6-Cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [6-cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizin-1-yl]acetate.

¹ H NMR (DMSO-d6): δ2.25(s, 3H), 3.80(s, 2H), 4.65(s, 2H), 6.80(dd, J=1.4, 9.3Hz, 1H), 7.35(d, J=8.5Hz, 1H), 7.55(dd, J=1.0, 9.3Hz, 1H), 7.65(dt, J=3.1, 8.8Hz, 1H), 7.75(dd, J=2.9, 9.3Hz, 1H), 7.95 (dd, J=5.4, 9.3 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 9.05 (t, J=1.0 Hz, 1H).

MS: ESI (+ve) (method A): 374 (M+H) ⁺ , retention time 10.0 min.

Examples 13 and 14: [6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizin-1-yl]acetic acid and [7-chloro-6-fluoro-3 -(4-Methoxyphenylsulfanyl)-2-methylindolizine-1 base]acetic acid

Preparations 13a and 14a: Ethyl [6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizin-1-yl]acetate and [7-chloro-6-fluoro- 3-(4-Methoxyphenylsulfanyl)-2-methylindolizine-1-yl]ethyl acetate

The title compound was prepared by the method of Preparation 2c using ethyl (6-fluoro-2-methylindolizine-1-yl)acetate and bis(4-methoxyphenyl)disulfide.

MS: ESI (+ve) (method B): retention time 4.5 min.

Preparations 13b and 14b: [6-Fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizin-1-yl]acetic acid and [7-chloro-6-fluoro-3- (4-Methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

[6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl] ethyl acetate and [7-chloro-6-fluoro-3-(4 A mixture of ethyl -methoxyphenylsulfanyl)-2-methylindolizin-1-yl]acetate (0.35 g) and methanol (8.0 mL) was treated with 1.0 M aqueous sodium hydroxide (2.5 mL) , and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with water, and acidified by adding glacial acetic acid. The mixture was extracted with dichloromethane, and the combined extracts were washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by preparative reverse-phase HPLC gradient elution with acetonitrile in water (organic modifier from 55% to 80%) to afford 0.20 g of [6-fluoro-3-( 4-methoxyphenylsulfanyl)-2-methylindolizin-1-yl]acetic acid and 0.006 g of [7-chloro-6-fluoro-3-(4-methoxy Phenylsulfanyl)-2-methylindolizine-1-yl]acetic acid.

[6-Fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

¹ H NMR (CDCl ₃ ): δ2.35(s, 3H), 3.70(s, 3H), 3.75(s, 2H), 6.70-6.75(m, 3H), 6.85(d, J=8.9Hz, 2H ), 7.30 (dd, J=5.2, 9.7 Hz, 1H), 8.10 (m, 1H).

MS: ESI (+ve) (method A): 346 (M+H) ⁺ , retention time 11.7 min.

[7-Chloro-6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid

¹ H NMR (CDCl ₃ ): δ2.35(s, 3H), 3.70(s, 3H), 3.75(s, 2H), 6.70(d, J=8.8Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 7.40 (d, J=7.1 Hz, 1H), 8.15 (d, J=5.1 Hz, 1H).

MS: ESI (+ve) (method A): 380 (M+H) ⁺ , retention time 12.5 min.

Example 15: [3-(4-Bromophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

Preparation 15a: Ethyl [3-(4-bromophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 2c using ethyl (6-fluoro-2-methylindolizin-1-yl)acetate and 4-bromothiophenol.

MS: ESI (+ve) (method B): retention time 4.9 min.

Preparation 15b: [3-(4-Bromophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparations 13b and 14b using ethyl [3-(4-bromophenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate.

¹ H NMR (CDCl ₃ ): δ2.30(s, 3H), 3.75(s, 2H), 6.65(d, J=8.6Hz, 2H), 6.75(m, 1H), 7.25(d, J=8.6 Hz, 2H), 7.35 (dd, J=5.3, 9.7Hz, 1H), 8.00 (m, 1H).

MS: ESI (+ve) (method A): 395 (M+H) ⁺ , retention time 12.9 min.

Example 16: [3-(4-Cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

Preparation 16a: 4,4'-Dithiodibenzenesulfonic acid, disodium salt

Prepared by the method of Smith et al. (J. Org. Chem., 1964, 29, 1484-1488).

Preparation 16b: 4,4'-Dithiodibenzenesulfonyl chloride

A mixture of 4,4'-dithiodibenzenesulfonic acid, disodium salt (6.2 g), phosphorus oxychloride (6.2 mL) and phosphorus pentachloride (3.1 g) was heated at reflux for 2 hours. The mixture was cooled to room temperature, diluted with dichloromethane, and poured into ice. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated with cyclohexane to give 3.5 g of the title compound as a light brown solid.

¹ H NMR (CDCl ₃ ): δ 7.70 (m, 4H), 8.00 (m, 4H).

Preparation 16c: Bis[(cyclopropyl-4-sulfonyl)benzene]disulfide

A solution of 4,4'-dithiodiphenylsulfonyl chloride (1.0 g) in dichloromethane (20 mL) was added dropwise to cyclopropylamine (0.4 mL), triethylamine (1.6 mL) and dichloromethane at 0 °C (15 mL), and the resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a mixture of dichloromethane and methanol (1:0 to 99:1 by volume) to obtain 1.1 g of the title compound as a pale yellow solid.

MS: ESI (+ve) (method B): 457 (M+H) ⁺ , retention time 3.7 min.

Preparation 16d: Ethyl [3-(4-cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate

The title compound was prepared by the method of Preparation 2c using ethyl (6-fluoro-2-methylindolizine-1-yl)acetate and bis[(cyclopropyl-4-sulfonyl)benzene]disulfide.

MS: ESI (+ve) (method B): 463 (M+H) ⁺ , retention time 4.1 min.

Preparation 16e: [3-(4-Cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetic acid

The title compound was prepared by the method of Preparation 1d using ethyl [3-(4-cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizin-1-yl]acetate.

¹ H NMR (CDCl ₃ ): δ0.55(m, 4H), 2.15(m, 1H), 2.30(s, 3H), 3.75(s, 2H), 4.95(brs, 1H), 6.80(m, 1H ), 6.90 (d, J = 8.6Hz, 2H), 7.35 (dd, J = 5.1, 9.7Hz, 1H), 7.65 (d, J = 8.6Hz, 2H), 8.00 (dd, J = 1.9, 5.1Hz , 1H).

MS: ESI (+ve) (method A): 435 (M+H) ⁺ , retention time 10.8 min.

Biological results:

The compounds of the above examples were tested in the above-mentioned CRTH2 radioligand binding assay; in the binding assay, the K1 values of the compounds were less than 100 nM. For example, the Ki values of the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 16 are 27, 0.2, 0.9, 29, 0.8, respectively , 57, 47, 0.4, 2.9, 1.7, 26, 7.2, 44, 23 and 0.6 nM. The compounds also typically have _IC50 values of less than 100 nM in functional assays of calcium flux. For example, the compounds of Examples 2, 3, 5 and 16 have _IC50 values of 6.6, 11, 8.9 and 22 nM, respectively.

Claims (8)

1. A compound selected from the group consisting of: [3-(2,4-Dichlorophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid, [6-fluoro-3-(2-fluoro-4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1 base]acetic acid, [6-fluoro-3-(4-methylsulfonyl-2-trifluoromethylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid, (R)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propanoic acid, (S)-2-[6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]propanoic acid, [3-(4-Ethylphenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid, [(Ethylaminobenzenesulfonyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid, [7-Chloro-6-fluoro-3-(4-methylsulfonylphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid, [3-(2-Chloro-4-methylsulfonylphenylsulfanyl)-7-cyano-2-methylindolizine-1-yl]acetic acid, [6-cyano-3-(4-methylsulfonylbenzyl)-2-methylindolizine-1-yl]acetic acid, [3-(4-Chlorobenzyl)-7-cyano-2-methylindolizine-1-yl]acetic acid, [6-cyano-3-(6-fluoroquinolin-2-ylmethyl)-2-methylindolizine-1-yl]acetic acid, [6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid, [7-Chloro-6-fluoro-3-(4-methoxyphenylsulfanyl)-2-methylindolizine-1-yl]acetic acid, [3-(4-Bromophenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid, [3-(4-Cyclopropylsulfamoylphenylsulfanyl)-6-fluoro-2-methylindolizine-1-yl]acetic acid and their salts, N-oxides, hydrates and solvates. 2. A compound of claim 1 for therapeutic use. 3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 4. Use of the compound of claim 1 for preparing a composition for treating asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome or allergic rhinobronchitis. 5. Use of the compound of claim 1 for the preparation of a composition for the treatment of atopic or non-atopic dermatitis, Crohn's disease, ulcerative colitis or irritable bowel disease. 6. A method of treating asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome or allergic rhinobronchitis comprising administering an effective amount of a compound of claim 1 to a patient suffering from said disease. 7. A method of treating atopic or non-atopic dermatitis, Crohn's disease, ulcerative colitis or irritable bowel disease, comprising administering an effective amount of the compound of claim 1 to a patient suffering from said disease. 8. The use or method of any one of claims 4 to 7, wherein the condition is selected from psoriasis, atopic and non-atopic dermatitis, Crohn's disease, ulcerative colitis and irritable bowel disease .